EP0280975B1 - Processes for the production of substituted benzaldehydes, and intermediate products obtained by these processes - Google Patents

Description

• a) 4-Amino-3,5-dibrombenzaldehyd oder ein cyclisches Acetal oder das Oxim davon mit einem Alkalimetall-nieder-alkoxid in Gegenwart von Kupfer und einem protonierbaren organischen Lösungsmittel umsetzt, das Reaktionsprodukt mit einem Methylierungsmittel behandelt und eine im Reaktionsprodukt enthaltene Acetal- oder Oximgruppe hydrolysiert; oder
• b) ein 4-Brom-2,6-di-(nieder-alkoxy)-N,N-dimethylanilin mit einem Metallierungsmittel und danach mit einem Formylierungsmittel umsetzt.

The invention relates to a process for the preparation of substituted benzaldehydes and new compounds used in this process. In particular, the invention relates to a process for the preparation of 4-dimethylamino-3,5-di- (lower alkoxy) benzaldehydes, characterized in that

• a) 4-amino-3,5-dibromobenzaldehyde or a cyclic acetal or the oxime thereof is reacted with an alkali metal lower alkoxide in the presence of copper and a protonatable organic solvent, the reaction product is treated with a methylating agent and an acetal contained in the reaction product or hydrolyzed oxime group; or
• b) a 4-bromo-2,6-di- (lower alkoxy) -N, N-dimethylaniline is reacted with a metalating agent and then with a formylating agent.

A lower alkoxy group and a lower alkanol are preferably straight-chain and contain up to 6 carbon atoms. A preferred alkoxy group is methoxy.

The reaction of the 4-amino-3,5-dibromobenzaldehyde or a cyclic acetal thereof or the oxime with an alkali metal alcoholate is expediently carried out at an elevated temperature, preferably at temperatures of approximately 80 ° C. The alkali alcoholate is expediently used in excess, e.g. a 15-20-fold molar excess is used. Copper can be used as a metal powder, but preferably a Cu (I) compound such as Cu₂O or a Cu (I) salt, in particular a halide such as copper (I) iodide, is used. The Cu (I) salt can be used in catalytic amounts, e.g. are used in amounts of 2-3 mol%, Cu₂O is expediently used in an equimolar amount. Suitable protonatable organic solvents are in particular dimethylformamide or nitrogen-containing organic solvents such as pyridine or collidine. In a preferred embodiment, a solvent mixture is used in which a solvent such as dimethylformamide predominates. A cyclic acetal of 4-amino-3,5-dibromobenzaldehyde is preferably used as the starting point. Examples of such cyclic acetals are the ethylene, 2,3-butylene and 2,2-dimethyl-1,3-propylene acetal. A preferred starting material is 4- (5,5-dimethyl-1,3-dioxan-2-yl) -2,6-dibromaniline.

Suitable methylating agents are reagents such as preferably formaldehyde / formic acid, but other methylating agents, e.g. Dimethyl sulfate can be used.

In process variant b), the metalating agents used are organic lithium compounds, such as lithium alkyls, for example methyl or butyl Li; or phenyl lithium; or magnesium compounds. Examples of formylating agents are dimethylformamide, orthoformate and N-formylmorpholine. The metalation reaction can take place under conditions known per se for the production of lithium or magnesium organic or Grignard compounds. In a preferred embodiment, this is set 4-Bromo-2,6-di-lower alkoxy) -N, N-dimethylaniline with butyllithium in hexane at about -10 ° C. Dimethylformamide is preferred as the formylating agent.

Another aspect of the invention relates to a process for the preparation of the cyclic acetals of 4-amino-3,5-dibromo-benzaldehyde, in particular 4- (5,5-dimethyl-m-dioxan-2-yl) -2,6- dibromaniline, and of 3,5-dibromo-4-amino-benzaldehyde oxime, which is characterized in that a cyclic acetal of p-nitrobenzaldehyde, in particular 2- (4-nitrophenyl) -5,5-dimethyl-1,3 -dioxane, or the 4-nitrobenzaldehyde oxime to a cyclic acetal of p-amino-benzaldehyde, in particular p- (5,5-dimethyl-1,3-dioxan-2-yl) aniline, or 4-amino-benzaldehyde oxime and the latter is brominated, or that p-nitrotoluene is reacted with a lower alkyl nitrite in the presence of a base to give p-aminobenzaldehyde oxime and the latter is brominated. The reduction of the p-nitrobenzaldehyde acetal to a p-amino-benzaldehyde acetal or the 4-nitrobenzaldehyde oxime to p-aminobenzaldehyde oxime is conveniently accomplished by catalytic hydrogenation, e.g. in the presence of Pt or Pd catalysts; or made with Raney-Ni. When p-nitrotoluene is reacted with a lower alkyl nitrite, isoamyl nitrite is preferably used as the base, preferably an alkali metal alcoholate, e.g. Sodium ethylate used in ethanol. The bromination can be carried out with elemental bromine in the presence of a proton acceptor such as butylene oxide.

Another aspect of the invention relates to a process for the preparation of 4-bromo-2,6-di- (lower alkoxy) -N, N-dimethylanilines, which is characterized in that a 2,6-di- (lower Alkoxy) aniline to a 4-bromo-2,6-di (lower alkoxy) aniline brominated and the latter methylated. The bromination can be carried out by treatment with elemental bromine in a solvent, for example a chlorinated hydrocarbon such as dichloromethane. Methylation can be accomplished by treatment with a methylating agent such as dimethyl sulfate.

The compounds obtained in the reactions described above
p- (5,5-dimethyl-1,3-dioxan-2-yl) aniline,
4- (5,5-dimethyl-1,3-dioxan-2-yl) -2,6-dibromaniline,
4-bromo-2,6-dimethoxyaniline,
4-bromo-2,6-dimethoxy-N, N-dimethylaniline,
4-amino-3,5-dibromobenzaldehyde oxime and
4-amino-3,5-dimethoxybenzaldehyde oxime
are new and also the subject of the invention.

The 4-dimethylamino-3,5-di- (lower alkoxy) benzaldehydes obtainable according to the invention are intermediate products for the production of benzylpyrimidines useful as pharmaceuticals, cf. e.g. German Offenlegungsschrift No. 2 443 682. The previously known production processes for these benzylpyrimidines are expensive. The present invention now makes it possible to produce these connections much more cost-effectively than previously. This is achieved by making the benzaldehyde derivatives required as key intermediates from cheap raw materials accessible in high yield using simple reactions.

The invention is further illustrated by the examples below. The temperatures are given in degrees Celsius.

example 1

A mixture of 765 g of 4-nitrobenzaldehyde, 537.5 g of 2,2-dimethyl-1,3-propanediol, 0.58 g of p-toluenesulfonic acid monohydrate and 2530 ml of toluene was heated under reflux for 15 hours until about 85 ml Had separated water and no educt could be detected. The reaction mixture was cooled and washed with 500 ml of water. The aqueous phase was tert with 1500 ml. Butyl methyl ether extracted, the extract washed with 1000 ml of saturated aqueous sodium chloride solution and the organic phases dried over sodium sulfate. The solvent was distilled off at 50 ° / 15 mbar and the residue was dried at 50 ° / 0.01 mbar. 1195.4 g (99%) of beige crystals of melting point 81-84 ° were obtained. The purity determined by gas chromatography was 98.5%. This crude product was recrystallized from n-hexane, whereby 1128 g (94%) of 2- (4-nitrophenyl) -5,5-dimethyl-1,3-dioxane were obtained as light yellow crystals of melting point 83-85 °. The purity determined by gas chromatography was 100%.

Example 2

A mixture consisting of 1125 g of 2- (4-nitrophenyl) -5,5-dimethyl-1,3-dioxane, 112.5 g of platinum on carbon and 11250 ml of tetrahydrofuran was at 25 ° with an H₂ pressure of 10 bar during Hydrogenated for 8 hours. The approach was worked up as follows:
All operations were carried out under N₂ fumigation. The catalyst was separated off by filtration through a dicaliter pad, the filtrate was freed from the solvent at 60 ° / 15 mbar and the residue was dried at 60 ° / 0.1 mbar. 945.2 g (96.2%) of 5,5-dimethyl-1,3-dioxan-2-yl) aniline were obtained as beige crystals of melting point 102-104 °.

Example 3

To a solution of 10.36 g of p- (5,5-dimethyl-1,3-dioxan-2-yl) aniline, 14.42 g of butylene oxide in 200 ml of dichloromethane were stirred with ice cooling with stirring within 1.5 hours 0-5 ° precooled solution of 16.78 g of bromine in 500 ml of dichloromethane was added dropwise. The reaction was completed by stirring at room temperature overnight. The reaction mixture 7.5 ml of 28% aqueous sodium hydroxide solution were added in succession at room temperature with stirring at room temperature to about 12 and 130 ml of 10% aqueous sodium thiosulfate solution within 15 minutes, the organic phase was separated off and the aqueous phase in succession with 2 portions of 250 ml Extracted dichloromethane. The combined organic phases were dried over 30 g of sodium sulfate, the solvent was distilled off at 50 ° / 15 mbar and the residue was dried at 50 ° / 0.01 mbar. 17.4 g (95.3%) of beige crystals of melting point 154-156 ° were obtained. The purity determined by gas chromatography was 88.3%. The crude product was recrystallized from ethanol and gave 12.8 g (70%) of 4- (5,5-dimethyl-1,3-dioxan-2-yl) -2,6-dibromanlin as white crystals with a melting point of 156-157 ° . The purity determined by gas chromatography was 100%.

Example 4

630 ml of solvent mixture were distilled off from a solution of 1235 ml of 30% methanolic sodium methylate solution and 450 ml of dimethylformamide with stirring and nitrogen sparging at 103-118 ° (bath temperature 120-140 °) within 45 minutes. A white precipitation (Na methylate) occurred towards the end of the distillation. Now the temperature was reduced to 80 ± 2 ° (bath temperature 90-92 °) and 16.6 g of copper (I) iodide (finely powdered) were added to the reaction mixture in one portion. About 5 g, 121.6 g of 4- (5,5-dimethyl-1,3-dioxan-2-yl) -2,6-dibromo-aniline were added in portions over 15 minutes. With good stirring, the reaction was continued for 3.5 hours at 80 ± 2 ° until the starting material could no longer be detected. The reaction mixture, cooled to room temperature, was poured onto 1050 ml of water while stirring and cooling, and heated to 60 ° for 4 hours. The mixture, cooled to room temperature, was stirred for 15 minutes with 5 g of activated carbon and 2200 ml of toluene and sucked over dicalite. The aqueous phase was extracted twice with 900 ml of toluene. The solvent was distilled off at 60 ° / 15 mbar and the residue was dried at 60 ° / 0.01 mbar. The residue (87.6 g of brownish oil) was refluxed with 400 g of 98% formic acid and 58 g of 37-40% aqueous formaldehyde solution for 180 minutes at 89-94 ° (bath temperature 92-102 °). Then 23 ml of 37% hydrochloric acid were added and the mixture was heated to reflux for a further 2 hours. The reaction mixture was freed from formaldehyde and formic acid at 55-60 ° / 15 mbar. The residue was diluted with 1140 ml of ice water, 81 ml of 28% aqueous sodium hydroxide solution were added, with stirring and cooling at 10-15 ° to pH 8.5, and the mixture was extracted with three times 800 ml of toluene. The organic phase was washed with 240 ml of saturated aqueous sodium chloride solution, dried over sodium sulfate, the solvent was distilled off at 60 ° / 15 mbar and the residue was dried at 60 ° / 0.1 mbar. The residue obtained was 67.1 g of yellow oil, which was distilled under high vacuum over a 25 cm Vigreux column. At 110-120 ° / 0.1 mbar, 54.4 g of 4- (dimethylamino) -3,5-dimethoxybenzaldehyde were obtained as a light yellow oil which crystallized on standing. The purity determined by gas chromatography was 98% (mp. 46-47 °).

Example 5

A solution of 78.9 g of bromine in 1 l of dichloromethane was added dropwise to a solution of 76.6 g of 2,6-dimethoxyaniline in 8 l of dichloromethane at about 1 ° in such a way that the reagent was relatively quick at the beginning (750 ml in 2 Hours) after which it was added more slowly to avoid overbromination. After about 6 hours, all of the reagent was added. The mixture was then stirred for 25 minutes. The reaction mixture was washed with 2 l of 1N sodium hydroxide solution and twice with 1.25 l of water each time, the washing solution was re-extracted with 2 portions to 1.25 l of dichloromethane and the combined organic phases were dried over sodium sulfate. The solvent was evaporated at a bath temperature of 50 ° and the residue was dried. The result was 114.2 g of 4-bromo-2,6-dimethoxyaniline as an amorphous, brown mass. The purity, determined by gas chromatography, was 97%. This crude product was dissolved in 300 ml of toluene and purified by filtration over 1 kg of silica gel 60 and elution with 16 l of toluene. The eluate was evaporated at a bath temperature of 80 ° and the residue was dried. 94.4 g of 4-bromo-2,6-dimethoxyaniline resulted as pale beige crystals with a melting point of 71-73 ° and a purity of 99% determined by gas chromatography.

Example 6

95.2 g of 4-bromo-2,6-dimethoxyaniline were added to a suspension of 136 g of sodium bicarbonate in 200 ml of water with vigorous stirring, and the suspension was cooled to 10 ° using an ice bath. Then 181 g of dimethyl sulfate were added in one portion and the heterogeneous mixture was stirred vigorously at 10 ° for 2.5 hours until no gas evolution and no starting material was detectable. The mixture was stirred until room temperature was reached, 90 ml of 25% aqueous ammonia solution were added and the mixture was stirred for a further hour. The reaction mixture was extracted with 360 ml of dichloromethane, the organic phase was treated with 450 ml of hydrochloric acid solution and the aqueous phase was washed with 180 ml of dichloromethane. Rühren68 ml of 28% aqueous sodium hydroxide solution was added dropwise to the hydrochloric acid, aqueous phase with stirring and cooling until pH 8.5 was reached and the product began to crystallize out. The suspension was cooled to 0 ° to complete the crystallization. The white crystals were filtered off with suction, washed neutral with 200 ml of ice water, dried for 3 hours at 50 ° / 15 mbar and overnight at 50 ° in a high vacuum. 100.4 g of 4-bromo-2,6-dimethoxy-N, N-dimethylaniline resulted as white crystals with a melting point of 90-91 °. The purity determined by gas chromatography was 100%.

Example 7

13 g of 4-bromo-2,6-dimethoxy-N, N-dimethylaniline were dissolved in 165 ml of ether under nitrogen. 50 g of butyllithium in hexane were added dropwise to the solution, which had cooled to -10 °, and the resulting white suspension was stirred at -10 ° for 30 minutes. With thorough mixing, a solution of 28.6 g of dimethylformamide in 250 ml of ether was added dropwise at the same temperature within 1 hour and the mixture was left to react for 4 hours at room temperature. The mixture was then concentrated to 20 g. Poured hydrochloric acid and 20 g of ice and hydrolyzed with good stirring for 1 hour (pH about 1.2). At 5-10 ° (cooling by ice) the aqueous phase was brought to pH 8.5 by adding about 20 ml of 28% sodium hydroxide solution. The aqueous phase was extracted with 480 ml of ether; the ether phase is washed with 120 ml of semi-saturated sodium chloride solution, dried over sodium sulfate and filtered off, the filtrate is evaporated in a water jet vacuum at a bath temperature of 50 ° and the residue is dried under high vacuum. This gave 10.5 g of 4- (dimethylamino) -3,5-dimethoxybenzaldehyde as an oil, which solidified to yellow crystals in the refrigerator. The purity determined by gas chromatography was 88.5%.

Example 8

13.6 g of 4-amino-benzaldehyde oxime were dissolved in 300 ml of glacial acetic acid while stirring. The temperature was lowered to 0-2 ° and a solution of 35.2 g of bromine in 100 ml of glacial acetic acid was added dropwise from the dropping funnel within 20 minutes so that the temperature did not exceed the range of 15-20 °. The reaction mixture was immediately poured onto 1000 ml of a 1: 1 mixture of ice / water and stirred for 30 minutes. The precipitated crystals were separated off and suspended in two 250 ml portions, ie totally with 500 ml of ice water, and sucked dry. The crystals were grown overnight at room temperature Dried over potassium hydroxide in a water jet vacuum to constant weight. 20 g of 3,5-dibromo-4-aminobenzaldehyde oxime were obtained as ocher-colored crystals of melting point 144-145 °. The purity determined by gas chromatography was 83%.

Example 9

810 ml of solvent mixture were distilled off from a mixture of 1527 ml of 30% methanolic sodium methylate solution and 562 ml of dimethylformamide until sodium methylate began to precipitate. After lowering the temperature to 80 ± 2 ° (bath = 82 °), 21.38 g of copper (I) iodide were added in one portion as a finely ground powder, the mixture taking on a deep blue color which, after 15 minutes of stirring, turned violet turned over. Within 5 minutes, portions of about 1.5 g total of 118 g of 3,5-dibromo-4-aminobenzaldehyde oxime were added and the mixture was stirred at 80 ° for 2 hours until neither starting material nor intermediate monomethoxy product could be detected. The reaction mixture, cooled to 60 °, was added to 2.5 kg of ice / water = 1: 1 within 15 minutes, the mixture was brought to 60 ° and left under stirring for 8 hours. The mixture was then poured into 1000 ml of ice-cooled concentrated aqueous hydrochloric acid with stirring. The neutral parts were extracted with two 1000 ml portions, ie a total of 2000 ml of toluene. With the addition of ice cubes, 700 ml of 28% aqueous sodium hydroxide solution were added to the aqueous acid phase at room temperature until the pH reached about 9-10, and the released 4-amino-3,5-dimethoxybenzaldehyde oxime in three portions of 1000 ml, ie totally extracted with 300 ml of toluene. To set muddy parts, 20 g of silica gel 60 was added and sucked over a dicalite pad. The clear, orange two-phase filtrate was separated from the water phase. The toluene phase was concentrated at 60 ° / 15 mbar and the residue was dried at 60 ° / 0.1 mbar until constant. 78.6 g of 4-amino-3,5-dimethoxybenzaldehyde oxime were obtained as a brown-yellow solid mass. The purity determined by gas chromatography was 66.54%.

Example 10

78.6 g of 4-amino-3,5-dimethoxybenzaldehyde oxime (crude product from Example 9) were mixed with 468 ml or 558 g of 98% formic acid and with 80.8 g of 37-40% aqueous formaldehyde solution and the mixture 2 1/4 Heated to reflux for hours until there was no more educt. Then 31.8 ml or 35.5 g of concentrated hydrochloric acid were added and the mixture was heated under reflux for a further 2 hours. The reaction mixture, cooled to room temperature, was freed from excess formaldehyde solution and formic acid at 55 ° / 15 mbar. 1380 g of ice water were added to the residue, and 62 ml of 28% aqueous sodium hydroxide solution were added with the addition of ice cubes at room temperature until a pH of 8.5 was reached. The released 4-dimethylamino-3,5-dimethoxybenzaldehyde was added in three 1000 ml portions, i.e. totally extracted with 3000 ml of toluene. The toluene phases were washed successively with 300 ml of saturated aqueous saline. The aqueous phases were discarded, the toluene phases were combined and dried over 200 g of sodium sulfate. The desiccant was filtered off with two 100 ml portions, i.e. totally slurried with 200 ml of toluene and vacuumed dry. The solvent of the filtrate was distilled off at 60 ° / 15 mbar and the residue was dried to constant weight at 60 ° / 0.1 mbar. 54.2 g of 4-dimethylamino-3,5-dimethoxybenzaldehyde were obtained as a tan oil with a purity of 96% determined by gas chromatography.

Example 11

14.3 g of copper (I) oxide were heated under argon with 370 ml of sodium methylate solution (2 mol) for 10 minutes with stirring under reflux and within 10 minutes with a solution 36.5 g of 4- (5,5-dimethyl-1,3-dioxan-2-yl) -2,6-dibromaniline in 200 ml of N, N-dimethylformamide. 175 ml of solvent were then distilled off. After stirring for 90 minutes at 80-108 °, the reaction mixture was cooled, rinsed with about 200 ml of methylene chloride in a 2 liter round bottom flask and rotated on a rotary evaporator at max. 6 ° / 30 mbar concentrated. The brown-red, solid residue was taken up in 750 ml of 3N sodium hydroxide solution, the suspension was stirred under reflux for 60 minutes, cooled to 60 °, 300 ml of ethyl acetate were added, the mixture was stirred for 10 minutes and filtered through a filter aid. The filter residue was washed three times with 100 ml of ethyl acetate, the aqueous phase was separated off and extracted twice more with 100 ml of ethyl acetate. The organic phases were washed in succession with 250 ml of water, dried over 50 g of magnesium sulfate, filtered, the filter residue was washed twice with 50 ml of ethyl acetate each time and the combined filtrates on a rotary evaporator at max. Concentrated at 35 ° / 30 mbar, 32.1 g of 4- (5,5-dimethyl-1,3-dioxan-2-yl) -2,6-dimethoxyaniline being obtained as the crude product. 31.6 g of the crude product thus obtained were refluxed with 140 ml of formic acid and 22.9 g of formaldehyde solution while stirring. The brown solution was cooled to 0 ° and washed four times with ice-cooling with 100 ml of methylene chloride, the organic extracts were extracted twice with 100 ml of 3N hydrochloric acid, the combined aqueous phases were in the course of 2 hours at 0-5 ° with 435 ml of sodium hydroxide solution (28%) adjusted to pH 11, the resulting emulsion extracted with 550 ml methylene chloride, the extracts washed individually with 250 ml cold water, the organic phase dried over 50 g magnesium sulfate, filtered through a glass filter with 40 g silica gel, the filter bed with six times 50 ml of methylene chloride each was washed and the combined filtrates were evaporated to constant weight in a rotary evaporator at 30 ° / 30 mbar. 15.6 g of 4-amino-3,5-dimethoxybenzaldehyde were obtained as a light yellow oil. The filter bed was washed three times with 100 ml of ether each combined filtrates were evaporated to constant weight in a rotary evaporator at 30 ° / 30 mbar, a further 1.9 g of reaction product being obtained.

Claims (11)

1. A process for the manufacture of 4-dimethylamino-3,5-di-(lower-alkoxy)benzaldehydes, characterized by

   a) reacting 4-amino-3,5-dibromobenzaldehyde or a cyclic acetal or the oxime thereof with an alkali metal lower-alkoxide in the presence of copper and a protonizable organic solvent, treating the reaction product with a methylating agent and hydrolyzing an acetal or oxime group present in the reaction product; or

   b) reacting a 4-bromo-2,6-di-(lower-alkoxy)-N,N-dimethyl-aniline with a metalating agent and thereafter with a formylating agent.
2. A process according to claim 1, characterized in that a Cu(I) salt is used in a).
3. A process according to claim 1, characterized in that 4-(5,5-dimethyl-1,3-dioxan-2-yl)-2,6-dibromoaniline is used as the cyclic acetal in a).
4. A process according to any one of claims 1-3, characterized in that the cyclic acetal of 4-amino-3,5-dibromo-benzaldehyde used in a) is prepared by reducing a cyclic acetal of p-nitrobenzaldehyde to a cyclic acetal of p-aminobenzaldehyde and brominating the latter compound.
5. A process according to claim 1, characterized in that the 3,5-dibromo-4-amino-benzaldehyde oxime used in a) is prepared by reducing 4-nitrobenzaldehyde oxime to 4-amino-benzaldehyde oxime and brominating the latter; or by reaction p-nitrotoluene with a lower-alkyl nitrite in the presence of a base and brominating the thus-obtained 4-aminobenzaldehyde oxime.
6. A process according to claim 1, characterized in that the 4-bromo-2,6-di-(lower-alkoxy)-N,N-dimethylaniline used in b) is prepared by brominating a 2,6-di-(lower-alkoxy)aniline to give a 4-bromo-2,6-di-(lower-alkoxy)aniline and methylating the latter compound.
7. A process according to claim 1, characterized in that an alkali metal methoxide is used as the alkali metal lower-alkoxide in a).
8. 4-(5,5-Dimethyl-1,3-dioxan-2yl)-2,6-dibromoaniline.
9. 4-Bromo-2,6-dimethoxy-N,N-dimethylaniline.
10. 4-Amino-3,5-dibrombenzaldehyde oxime.
11. 4-Amino-3,5-dimethoxybenzaldehyde oxime.